Associations Between Obesity and the Effectiveness of Anti-Tumor Necrosis Factor-α Agents in Inflammatory Bowel Disease Patients: A Literature Review and Meta-analysis.

Background: A total of 15% to 40% of adult inflammatory bowel disease (IBD) patients are obese. The influence of obesity on anti-tumor necrosis factor-α (anti-TNF-α) treatment in IBD patients is not consistent. Objective: To determine the association between obesity and the efficacy of anti-TNF treatment in IBD patients. Methods: We performed a systematic search from January 1990 through November 2019 on MEDLINE, Web of Science, Google Scholar, ClinicalTrials.gov, and Cochrane library. We included randomized controlled trials and observational cohort studies that investigated the outcome of anti-TNF treatment in IBD patients with stratification according to body mass index or body weight. The odds ratio (OR) and its 95% CI were calculated. Results: In this pooled meta-analysis, we observed that obesity increased the odds of failure of anti-TNF therapy (OR = 1.195; 95% CI = 1.034-1.380; P = 0.015; I2 = 47.8%). After performing subgroup analyses, obesity was associated with higher odds of anti-TNF treatment failure in ulcerative colitis (UC) patients (OR = 1.413; 95% CI = 1.008-1.980; P = 0.045; I2 = 20.0%) but not in Crohn's disease patients (OR = 1.099; 95% CI = 0.928-1.300). Obesity significantly increased the odds of treatment failure of both dose-fixed and weight-based anti-TNF agents (OR = 1.121, 95% CI = 1.027-1.224, P = 0.011, and OR = 1.449, 95% CI = 1.006-2.087, P = 0.046, respectively). Conclusion and Relevance: In our meta-analysis, obesity was associated with the inferior response of anti-TNF treatments in UC patients. Clinicians should be aware that obese UC patients may require higher doses in anti-TNF treatment.

WNT5A transforms intestinal CD8αα⁺ IELs into an unconventional phenotype with pro-inflammatory features.

BACKGROUND: Intestinal intraepithelial lymphocytes that reside within the epithelium of the intestine form one of the main branches of the immune system. A majority of IELs express CD8α homodimer together with other molecules associated with immune regulation. Growing evidence points to the WNT signaling pathway as a pivotal piece in the immune balance and focuses on its direct regulation in intestinal epithelium. Therefore we decided to investigate its role in IELs' immune status determination. METHOD: DSS colitis was induced in male C57BL mice. IELs were isolated from colon samples using mechanical dissociation followed by percoll gradient purification and Magnetic-activated cell sorting. Phenotype and cytokine production and condition with Wnts were analyzed by flow cytometry, real-time PCR or ELISA. Proliferation of lymphocytes were evaluated using CFSE dilution. Cell responses after WNT pathway interference were also evaluated. RESULTS: Non-canonical WNT pathway elements represented by FZD5, WNT5A and NFATc1 were remarkably elevated in colitis IELs. The non-canonical WNT5A skewed them into a pro-inflammatory category as measured by inhibitory cell surface marker LAG3, LY49E, NKG2A and activated marker CD69 and FASL. Gaining of a pro-inflammatory marker was correlated with increased IFN-γ production but not TNF whilst decreased TGF-ß and IL-10. Both interrupting WNT5A/PKC pathway and adding canonical WNT stimulants could curtail its immune-activating effect. CONCLUSION: Canonical and non-canonical WNT signals act in opposing manners concerning determining CD8αα(+) IELs immune status. Targeting non-canonical WNT pathway may be promising in tackling inflammatory bowel disease.

1,25-hydroxyvitamin D relieves colitis in rats via down-regulation of toll-like receptor 9 expression.

AIM: To investigate the therapeutic and immunoregulatory effects of 1,25-dihydroxyvitamin D (1,25(OH)D3) on 2,4,6-trinitrobenzenesulfonic acid (TNBS) -induced colitis in rats. METHODS: Experimental colitis induced by enema administration of TNBS plus ethanol was treated with 5-aminosalicylic acid (5-ASA) and/or 1,25(OH)D3. Disease activity was measured using the disease activation index (DAI), colon macroscopic damage index (CMDI), histological colonic damage score, and myeloperoxidase (MPO) activity. The expression of toll-like receptor 9 (TLR9) in the colon was determined by reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: Rats with TNBS-induced colitis had significantly elevated DAI, CMDI, histological colonic damage score, and MPO activity (all P<0.001) compared to rats without colitis. Treatment with 5-ASA or 1,25(OH)D3 ameliorated colitis by lowering CMDI (P=0.049, P=0.040, respectively), histological colonic damage score (P=0.010, P=0.005, respectively), and MPO activity (P=0.0003, P=0.0013, respectively) compared with the TNBS group. Combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased MPO activity (P=0.003). 1,25(OH)D3 attenuated colitis without causing hypercalcemia or renal insufficiency. TNBS significantly increased the number of TLR9 positive cells compared to control (P<0.010), while 5-ASA, 1,25(OH)D3, and combined treatment with 5-ASA and 1,25(OH)D3 significantly decreased it compared to TNBS group (all P<0.010). In TNBS group a moderate correlation was observed between MPO activity and the number of TLR9-positive cells (r=0.654, P<0.001). CONCLUSION: TLR9 expression correlates with the extent of inflammation in TNBS-induced colitis. 1,25(OH)D3 relieves this inflammation possibly by decreasing TLR9 expression.